Electrographic flow (EGF) mapping reveals sex-based differences in EGF patterns with women concentrated in phenotypes that benefit from EGF-guided ablation.
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Electrographic flow (EGF) mapping reveals sex-based differences in EGF patterns with women concentrated in phenotypes that benefit from EGF-guided ablation - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Search Log in Primary site navigation Search Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice J Interv Card Electrophysiol . 2026 Jan 7;69(4):637–650. doi: 10.1007/s10840-025-02184-8 Electrographic flow (EGF) mapping reveals sex-based differences in EGF patterns with women concentrated in phenotypes that benefit from EGF-guided ablation Ilana Kutinsky 1, # , Kent R Nilsson 2, 3, # , Matthew Mrlik 4 , Melissa H Kong 5 , Nishaki Mehta 1 , Steven Castellano 5, ✉ Author information Article notes Copyright and License information 1 Department of Electrophysiology, Corewell Health William Beaumont University Hospital, Royal Oak, MI USA 2 Department of Cardiac Electrophysiology, Piedmont Heart Institute, Athens, GA USA 3 Augusta University-University of Georgia, Athens, GA USA 4 College of Medicine, California Northstate University, Elk Grove, CA USA 5 Cortex, Inc., Menlo Park, CA USA ✉ Corresponding author. # Contributed equally. Received 2025 Mar 23; Accepted 2025 Nov 5; Issue date 2026. © The Author(s) 2026 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ . PMC Copyright notice PMCID: PMC13221358 PMID: 41498861 Abstract Background Electrographic flow (EGF) mapping allows for the near real-time visualization of atrial wavefront propagation. Two factors have been found to be associated with higher rates of atrial fibrillation (AF) recurrence: presence of active extra-pulmonary vein (PV) sources and low electrographic flow consistency (EGFC) representing chaotic flow and abnormal atrial substrate. Based on these characteristics, EGF phenotypes have been identified: Type I patients have no sources + high EGFC, Type II have sources + high EGFC, Type III have sources + low EGFC, and Type IV have no sources + low EGFC. Objective Determine the sex differences in EGF phenotypes and post-ablation outcomes. Methods Patients were pooled from three prospective clinical trials: FLOW-AF , EVAL-AF , and the AF-FLOW Global Registry . From these trials, 104 persistent AF (PeAF) or long-standing PeAF patients underwent EGF mapping in 5 standardized, biatrial basket positions. Phenotyping into one of the 4 types was performed from post-PVI maps, and patients were followed for up to 12 months post-procedure, which included PVI-only and PVI + EGF-guided source ablation procedures. Outcomes were compared by chi-square tests, z -tests of proportions, logistic regression, and cox proportional models. Results There were 30 (29%) female patients with mean age 70 ± 8 years and 74 (71%) males with mean age 64 ± 10 years. There was no significant difference in left atrial dimension, left ventricular ejection fraction, or number of prior ablations between men and women. Men and women had distinct phenotype distributions ( p = 0.007). Women had more sources and higher EGFC so were more likely than men to present as Type II (43% vs. 20%, p = 0.016), including when controlling for confounders (aOR 3.17, p = 0.024). Outcomes of these Type II patients were most improved by PVI + EGF-guided ablation when compared to PVI-only (91% vs. 50%, p = 0.038) without differences in intra-phenotype responsiveness to treatment by sex or intragroup hazard ratios by sex. Trends in phenotype differences of women vs. men were also present among those with other factors that increased CHA 2 DS 2 -VASc scores generally. Conclusions Female patients with PeAF are more likely to have extra-PV sources but healthy underlying substrate (Type II), which responds favorably to PVI + targeted source ablation. Ablation strategies should consequently target an individual’s mechanism of disease. Trial registration numbers FLOW-AF : NCT04473963 , FLOW EVAL-AF : NCT06260670 , AF-FLOW Global Registry: NCT05481359 . Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s10840-025-02184-8. Keywords: Arrhythmias, Cardiac, Atrial fibrillation, Pulmonary vein ablation, Electrographic flow mapping, Panoramic mapping, Basket catheter, Sex differences Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with significant morbidity and mortality. Pulmonary vein isolation (PVI) has been established as a cornerstone of AF management and is particularly effective in the treatment of paroxysmal AF (PAF), where single procedure rates of freedom from AF (FFAF) approach 70–85% at 1-year, depending upon mapping techniques, energy source, and method of delivery [ 1 – 7 ]. For persistent AF (PeAF), success rates with ablation are more modest. Multiple randomized controlled trials have demonstrated 1-year FFAF rates of 55–60%, irrespective of additional endocardial substrate modification, suggesting that prescriptive additional lesion sets add little benefit to PVI alone [ 6 ]. Women have generally demonstrated higher rates of AF recurrence following ablation compared to men despite having lower overall incidence of AF and a later average age of AF detection [ 8 – 11 ]. Women therefore often undergo ablation later in life and present with a greater burden of comorbid conditions, such as valvular heart disease, hypertension, and heart failure [ 10 , 12 , 13 ]. Women with AF are also less likely to be referred to for cardiac ablation than men and try more anti-arrhythmic drugs prior to ablation [ 14 , 15 ]. Emerging evidence additionally suggests that women may have more extensive atrial remodeling at the time of ablation. This remodeling may occur more commonly in women due to higher levels of inflammation and pericardial fat mediating oxidative stress and myofibroblast activation [ 10 , 16 – 19 ]. Consequently, women’s atria at the time of ablation have been characterized by greater fibrosis, more low-voltage areas, more complex fractionated signals, and higher LA stiffness [ 20 – 23 ], though these observations have not consistently been tied to increased rates of recurrence. Whether disparities in AF ablation outcomes by sex are due to biological differences in atrial substrate, differences in baseline clinical profiles, or delayed access to treatment remains an open question [ 23 ]. A deeper understanding of sex-specific AF pathophysiology and its influence on ablation success is therefore essential to advancing equitable and effective AF management. To increase knowledge of wavefront propagation patterns in AF, various mapping techniques have been developed to identify non-pulmonary vein (PV) drivers/triggers of AF with limited success to date. Electrographic flow (EGF) mapping is a novel, 4D, non-phased mapping technique that uses both spatial and temporal reconstructions of multiple, panoramic, simultaneously recorded endocardial electrograms. From the generated maps, temporally unstable sources of AF can be identified, and insights can be gained about the overall conduction patterns through the substrate [ 24 – 27 ]. Source activity (SAC) quantifies the percentage of time when a source serves as an origin of excitation, while electrographic flow consistency (EGFC) quantifies atrial substrate health by measuring coherence of flow vectors through the endocardium. It also has modest correlation to the percent of tissue with healthy bipolar voltage [ 28 , 29 ]. In an effort to further define a potential mechanistic explanation as to why women have worse outcomes following ablation compared with men despite following similar prescribed ablation lesion sets (e.g., PVI and posterior wall isolation), we look at all PeAF and long-standing PeAF (LS-PeAF) patients who underwent prospective EGF mapping in AF to determine the sex differences in EGF-based AF phenotype distributions, as well as differences in 1-year post-ablation outcomes. These same patients were further studied for trends in EGF phenotypes related to CHA 2 DS 2 -VASc scores more generally. Methods Study overview Details of trial design and rationale have been previously described for FLOW-AF (ClinicalTrials.gov identifier number NCT04473963 ) [ 30 ], FLOW EVAL-AF ( NCT06260670 ) [ 28 ], and the AF-FLOW Global Registry ( NCT05481359 ) [ 29 ], which have been outlined previously. Overall, four patient phenotypes were first characterized from FLOW-AF based on physiologic mechanism of AF and recurrence rate post-PVI: (1) Type I patients have no active sources and high EGFC; (2) Type II have active sources and high EGFC; (3) Type III have active sources and low EGFC; and (4) Type IV have no active sources and low EGFC [ 31 , 32 ]. The AF-FLOW Global Registry subsequently demonstrated the reproducibility of these phenotype-based outcomes among PVI-only and PVI + EGF-guided ablation patients in an open registry format that was also expanded to include PAF patients [ 29 , 33 ]. FLOW EVAL-AF additionally studied maps in multiple rhythms and explored how EGF metrics including EGFC changed between AF and SR [ 28 , 34 , 35 ]. Here, patients from all three studies were pooled and analyzed chiefly by sex and treatment modality. A breakdown of the number of patients in each grouping is shown in Supplementary Table 1 . PVI ablation procedure All procedures were performed under sedation after obtaining informed consent. Patients underwent 3-dimensional electroanatomic mapping with either Ensite NavX (Abbott, Abbott Park, IL) or CARTO (Biosense Webster, Diamond Bar, CA), followed by PVI using an irrigated tip radiofrequency ablation catheter. Ablation catheter power and temperature settings were at the operator’s discretion. Intravenous heparin was administered for systemic anticoagulation to maintain an activated clotting time > 300 s prior to insertion of the 64-pole basket mapping catheter. For any ablation of PVs, confirmation of PVI (entrance or exit block) was performed after a mandatory minimum 20-min wait or testing with adenosine following the last radiofrequency application. EGF mapping EGF mapping was performed both pre- and post-PVI using the Ablamap® v9.0.4-v11.1.0.56 software (Ablacon, Wheat Ridge, CO). Unipolar electrograms were recorded using with 50 mm or 60 mm commercially available 64-electrode basket mapping catheters (FIRMap™, Abbott, Abbott Park, IL) connected to a proprietary, CE-marked recording system (EP Map, Herdecke, Germany). Patients were required not to have pacemakers to receive EGF mapping. Each recording was 1-min long, and the unipolar signals were processed using a proprietary algorithm to remove the QRS complex, noise, baseline fluctuations, and far-field signals. Using a biharmonic spline interpolation based on Green’s function, the electrical field was estimated, and a Horn-Schunck flow estimation of the Green’s interpolation frames was performed to visualize atrial wavefront propagation over time. Haines et al. published an in-depth explanation of the theoretical basis for EGF mapping including details of the EGF mapping algorithm [ 24 ], which was summarized by Castellano and Kong [ 26 ]. The dominant patterns of wavefront propagation over time are displayed as flow vectors in EGF Segment Maps, enabling the visualization of origins of excitation representing extra-PV AF triggers called sources. Active sources exhibit divergent flow fields that can only be detected in AF [ 28 ]. EGF mapping was generally performed by obtaining 1-min recordings from the 64-pole basket catheter placed in multiple standardized positions within each atrium as well as additional recordings after any source ablations to confirm elimination. In the left atrium (LA), there were typically two standardized basket positions: (1) posterosuperior LA with the dome of the basket aiming toward the left PVs and LA appendage (LAA) and (2) lateral LA with basket dome pointing toward LAA and the mitral valve. In the right atrium (RA), there were generally three standardized basket positions: (1) superior vena cava (SVC)/RA junction with basket position halfway into the SVC, (2) central RA with basket dome pointing to SVC with vertical catheter shaft orientation and basket expanded to fill RA, and (3) anterolateral RA with basket dome pointing to RA appendage and tricuspid valve and catheter deflected anterior and lateral from SVC. Mapping in additional basket positions in either atrium was performed if necessary to obtain complete endocardial atrial coverage. EGF-guided ablation If EGF mapping identified an extra-PV source with a SAC ≥ 26.5%, based on the prespecified threshold for clinical significance, EGF-guided ablation at the target location of the focal source was required for treatment group patients, though not in unablated control group patients who received PVI-only treatment. All ablations were performed with an open-irrigated radiofrequency ablation catheter via resetting at the electrode location of EGF-identified source. Catheter power and temperature settings were determined at the operator’s discretion. Operators also had the ability to refuse to ablate at certain locations for safety concerns, such as in proximity to the esophagus, phrenic nerve, or sinus node. Post-ablation, repeat EGF mapping was recommended to confirm elimination of the leading source via reduction of SAC to < 26.5%. If additional sources were unmasked during repeat mapping, additional ablation was advised until identified sources were eliminated. EGFC calculations from EGF maps EGFC was computed for each recording as the Euclidean norm of vector field estimates across all recorded basket positions over time, providing a measure of the overall average flow magnitude in arbitrary units. Electrodes with low contact—defined as having peak cross-correlation with any adjacent channel at a time lag of 5 to 50 ms in fewer than 70% of recording segments—were excluded from the EGFC calculation due to their tendency to produce artificially low local EGFC values at these non-contacting electrode positions. The methods for assessing atrial contact are detailed by Nilsson et. al [ 29 ]. After calculating EGFC for each recording, the EGFCs from all of a patient’s recordings in each recording position during a given rhythm were first averaged to compute positional EGFC means per patient. These positional EGFCs were then averaged within each atrium to generate a mean EGFC per atrium per patient. Such a method allowed all recording positions to be given equal weight and was found to be more predictive of recurrence than methods that incorporated regional variance [ 36 ]. Each patient’s two atrial EGFCs were then averaged again to generate a global EGFC per patient. When generated from AF recordings, this overall mean EGFC was employed in phenotyping with 0.62 established as the cutoff between high and low EGFC [ 31 ]. When no AF recordings were available due to non-inducibility, the mean EGFC was computed in SR and converted to an AF EGFC using a linear equation developed previously [ 28 ]. SR maps were used to derive global EGFC in 8 of the 104 patients. Global EGFC status (high vs. low) and source presence (SAC ≥ 26.5% vs. no SAC ≥ 26.5%) were then used collectively to determine patient phenotypes based on mechanism of disease. Statistical analysis Summary data are expressed as mean value ± standard deviation. Group comparisons for continuous variables were performed using two-tailed, independent t -tests. Comparisons of proportions were assessed using z -tests for proportions when two proportions were directly compared and Pearson’s chi-square tests when distributions were compared. To evaluate multivariate associations between patient characteristics, linear regression models were used for continuous outcomes and binary logistic regression models for phenotype classification. In the latter, the presence of each phenotype was treated as the outcome (coded as 1), with all other phenotypes grouped as the reference category (coded as 0). Models included relevant covariates such as age, LAD, LVEF, and clinical comorbidities. Adjusted beta coefficients ( β ) or adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were reported. Sex-based differences in the time to arrhythmia recurrence were assessed using Cox proportional hazards models. Separate models were fit within three clinically defined patient groups: (1) no source patients, (2) source patients after PVI-only, and (3) source patients after PVI + EGF-guided ablation. Stratification by patient phenotype was not employed due to data scarcity. For each group, Cox models were constructed using sex as a binary covariate (0 = male, 1 = female), adjusting for age, LAD, LVEF, and comorbidities. Results are reported as hazard ratios with corresponding 95% CIs and p -values. Patients were included if they experienced at least one recurrence event (AF or AF/AFL/AT) and if both sexes were represented within the group. The proportional hazards assumption was tested and not violated in any model. All analyses were performed using Python (version 3.12.3) with statistical calculations performed using the SciPy (version 1.12.0) package and statistical modeling conducted using the statsmodels (version 0.14.4) and lifelines (version 0.30.0) packages. A two-sided p -value < 0.05 was considered statistically significant in all cases. Results Demographics reveal woman presented for AF ablation at a higher age A total of 104 PeAF and LS-PeAF patients were prospectively mapped across three studies: FLOW-AF , FLOW EVAL-AF , and the AF-FLOW Global Registry. Across the pooled cohort, there were 74 (72%) male and 30 (28%) female patients. Patient baseline demographics are shown in Table 1 . Women were older but had less history of transient ischemic attack (TIA)/stroke. They also had higher CHA 2 DS 2 -VASc differences but not significantly higher CHA 2 DS 2 -VA scores. There was no difference between men and women in left atrial dimension, left ventricular ejection fraction, AF duration, number of prior ablations, and patient history of other exacerbating diseases. Table 1. Patient demographics Demographic factor Males ( n = 74) Females ( n = 30) p -value Age (years) 63.5 ± 10.0 70.2 ± 7.7 0.0016 Left atrial dimension (cm) 4.59 ± 0.62 4.34 ± 0.51 0.057 Left ventricular ejection fraction (%) 55.6 ± 7.2 57.0 ± 7.0 0.37 AF duration (years) 5.8 ± 3.0 5.7 ± 2.2 0.87 Number of prior ablations 1.19 ± 0.40 1.14 ± 0.36 0.56 CHA 2 DS 2 -VASc 2.08 ± 1.45 3.38 ± 1.01 < 0.0001 CHA 2 DS 2 -VA 2.08 ± 1.45 2.38 ± 1.01 0.30 Congestive heart failure history 7/74 (9%) 7/30 (23%) 0.060 Hypertension history 53/74 (72%) 24/30 (80%) 0.38 Diabetes mellitus history 15/74 (20%) 4/30 (13%) 0.41 TIA/stroke history 9/74 (12%) 0/30 (0%) 0.046 Vascular disease history 17/74 (23%) 5/30 (17%) 0.48 Atrial flutter history 16/74 (22%) 5/30 (17%) 0.57 Open in a new tab Male and female baseline demographics are shown alongside p -value comparing the two cohorts. Significant results are bolded EGF metrics and phenotyping show women are more likely to have healthy substrate but also extra-pulmonary vein sources Across all EGF maps, maximum SAC in AF and overall mean EGFC were computed for all patients. Men had SAC 23 ± 8% while women had SAC 25 ± 10% ( p = 0.38), and EGFC was 0.55 ± 0.08 in men vs. 0.59 ± 0.11 for women ( p = 0.030). In multivariable linear regression models adjusting for age, LAD, LVEF, and comorbidities including CHF and TIA/stroke, female sex remained significantly associated with EGFC (adjusted β = 0.04, 95% CI 0.01–0.08, p = 0.036) but not a greater SAC (adjusted β = 3.29, 95% CI −3.50–10.1, p = 0.34). Women accordingly had a nonsignificantly higher SAC and significantly higher EGFC, as shown in Fig. 1 . Fig. 1. Open in a new tab Source activity and EGFC by sex. Mean and standard deviation are shown. A Source activity was nonsignificantly higher in women vs. men. B Global EGFC was significantly higher in women vs. men Though women did not have a significantly higher maximum SAC across all AF recordings, women were more likely than men to have extra-pulmonary vein (PV) sources with SAC ≥ 26.5% in AF: there was an average of 1.3 sources per woman and 1.0 sources per man ( p = 0.011). This trend was upheld in a multivariable linear regression model adjusting for confounders including age and comorbidities (adjusted β = 0.26, 95% CI 0.03–0.49, p = 0.030). Consequently, women with PeAF demonstrated both healthier atrial substrate and more extra pulmonary vein sources than men. The distribution of these sources across the atria is shown in Fig. 2 . Sources were most concentrated near the SVC/RA junction and the LAA with 16% of all sources and 28% of LA sources located on the posterior wall. When comparing source locations between men and women, men had 52% of sources in the LA while women had 63% in the LA ( p = 0.28). Moreover, no individual anatomical location showed a significant preponderance of sources from either sex. The preponderance of male vs. female sources at each anatomical location remained nonsignificantly different when adjusting for confounders via logistic regression. Fig. 2. Open in a new tab Anatomic distribution of EGF-identified sources by sex. Source locations are shown on a schematic of the left and right atria. Sources in males are shown as orange circles; sources in women are shown as purple triangles. There was no significant difference in the percentage of male vs. female sources at any anatomical location (numbered). A total of 16% of sources were on the posterior wall. AP, anteroposterior; PA, posteroanterior; SVC, superior vena cava; IVC, inferior vena cava; RSPV, right superior pulmonary vein; LSPV, left superior pulmonary vein; LIPV, left inferior pulmonary vein; RIPV, right inferior pulmonary vein All patients were subsequently phenotyped based on their source presence and global EGFC using the cutoffs determined in FLOW-AF [ 31 ]: SAC ≥ 26.5% and EGFC ≥ 0.62, which together established four phenotypes. Example EGF maps from representative patients of each phenotype are shown in Fig. 3 . Fig. 3. Open in a new tab EGF maps by phenotype. The four phenotypes were characterized based on the presence or absence of EGF-identified sources coupled with the presence of high or low EGFC. Looking at the EGF Summary Maps (top row), active sources appear as red spots that get redder with higher SAC, and EGFC is visualized as consistency of flow direction over time with more consistent flow represented by longer vector length. On the EGF Segment Maps (bottom row), which characterize only a 2-s segment of the 1-min recording aggregated in the Summary Map, a source that is active during the particular 2-s segment shown appears yellow. EGFC is displayed with higher flow consistency represented in magenta and more disorganized flow appearing bluer Overall, 70% of women and 58% of men had at least one source above the 26.5% threshold, while 50% of women and 34% of men had high global EGFC greater than 0.62 representing normal conduction. When examining the combination of source status and EGFC status by sex, women exhibited a distinct phenotypic distribution that significantly differed from that of men ( p = 0.0074), as shown in Fig. 4 . Phenotype fractions by sex was as follows: 10/74 (14%) male and 2/30 (7%) female Type Is, 15/74 (20%) male and 13/30 (43%) female Type IIs, 28/74 (38%) male and 8/30 (27%) female Type IIIs, and 21/74 (28%) male and 7/30 (23%) female Type IVs. Most notably among the distribution differences, women were more than twice as likely as men to have a Type II phenotype (43% vs. 20%, p = 0.016). Fig. 4. Open in a new tab Phenotype distribution by sex. Fraction and standard deviation are shown. Type I patients consisted of 14% of men and 7% of women; Type II, 20% of men and 43% of women; Type III, 38% of men and 27% of women; and Type IV, 28% of men and 23% of women. Women were 2.1 times more likely than men to be Type II Binary logistic regression models for each phenotype were also performed to assess the independent association of sex with each phenotypic classification while adjusting for the demographic factors of age, LVEF, LAD, and comorbidities including CHF history and TIA/stroke history. Female sex was again associated with an increased relative risk of being Type II (aOR 3.17, 95% CI 1.17–8.61, p = 0.024). However, female sex was not associated with an increased or decreased risk of being Type I (aOR 0.24, 95% CI 0.03–2.04, p = 0.19), Type III (aOR 0.83, 95% CI 0.30–2.29, p = 0.72), or Type IV (aOR 0.58, 95% CI 0.20–1.69, p = 0.32). Outcomes show largest improvement in 12-month freedom from AF recurrence among Type II patients that are concentrated in women Two study arms were present in FLOW-AF and the AF-FLOW Global Registry. In FLOW-AF , patients were randomized to PVI + EGF-guided ablation treatment vs. PVI-only control if they fell in the phenotypes containing extra-PV sources (Type II and Type III), while patients in the AF-FLOW Global Registry had treatment based on physician discretion. Across both studies, patients with no sources received PVI-only, which was the recommended treatment for their phenotypes because their SAC was below the clinically significant threshold at the time. Of note, EVAL-AF patients did not receive follow-up visits per the trial protocol and thus have no available post-ablation outcomes. Outcomes in men vs. women based on treatment modality and sex are shown in Fig. 5 . Among PVI-only patients, women had nonsignificantly lower FFAF than men (55% vs. 47%, p = 0.58). These can be further broken down into those without sources and those with sources. Among patients without sources, men had 68% FFAF vs. 56% FFAF in women ( p = 0.50). Among PVI-only patients with sources, men had 33% FFAF and women had 40% FFAF ( p = 0.73). All source patients also had higher FFAF upon receiving PVI + EGF-guided source ablation vs. PVI-only, creating a net 27% absolute increase in FFAF ( p = 0.043). Among these optimally treated patients, men and women again had nonsignificant differences in FFAF with men having 55% FFAF and women having 88% FFAF ( p = 0.097). Therefore, no significant outcome differences were observed within any patient arm between the two sexes; moreover, FFAF differences by sex that did appear were predominantly tied to the existing phenotype differences between men and women: men had better outcomes among no source patients because a larger percentage of them were Type I instead of Type IV, and women had better outcomes among source patients because a larger percentage of them were Type II instead of Type III. Fig. 5. Open in a new tab FFAF rate by treatment assignment and sex. Fraction and standard deviation are shown. The major consistent trend across both sexes was improved FFAF from PVI + source ablation vs. PVI-only among patients with sources. Within each treatment group, outcome differences by sex were nonsignificant and occurred as a result of phenotype differences with healthier substrate predominantly among male no source patients and female source patients FFAF was next assessed by phenotype to account for the additional effect of atrial substrate on recurrence. For patients with no active sources (Types I and IV), higher rates of recurrence were seen in patients with lower EGFC: Type I patients with high EGFC had 100% (10/10) FFAF vs. 50% (12/24) FFAF in Type IV patients with low EGFC ( p = 0.005). Similarly, patients with sources had lower recurrence rates when they had concomitant high EGFC. Type II patients had 71% (15/21) FFAF vs. 38% FFAF (13/34) in Type III patients ( p = 0.017). Moreover, among those with EGF-identified sources who received PVI-only, Type II patients with high EGFC had 50% (5/10) FFAF vs. 27% (4/15) FFAF in Type III patients with low EGFC ( p = 0.23). Among the Type II and Type III patients receiving PVI + EGF-guided ablation, FFAF was 91% (10/11) in Type II vs. 47% (9/19) in Type III ( p = 0.017). Type II patients therefore had an absolute increase in FFAF of 41% from 50 to 91%, ( p = 0.038), while Type III patients had an absolute increase in FFAF of 20% from 27 to 47% ( p = 0.22). Termination also occurred after source ablation in 27% (3/11) of Type II vs. 5% (1/19) of Type III PVI + EGF-guided source ablation patients ( p = 0.087). FFAF by patient phenotype and treatment modality is shown in Fig. 6 . Fig. 6. Open in a new tab FFAF by phenotype. All patients across all three clinical trials are shown. Slate colored bars signify PVI-only treatment while green hashed bars signify PVI + EGF-guided ablation. Women were more concentrated in Type II patients than men, which had the largest improvement from EGF-guided ablation in addition to PVI There were no significant differences in these outcomes by sex within any combination of phenotype and treatment assignment. The breakdown of these outcomes by sex is shown in Fig. 7 . A multinomial logistic mixed-effects model further showed phenotype to have a 12-fold larger effect size on recurrence likelihood than sex. Of note, there was data scarcity of Type I women who received PVI and of Type III women who received optimal treatment of PVI + EGF-guided ablation whereby there were only n = 2 patients with 12-month outcomes in each of these groupings. All other categories had n ≥ 5. Fig. 7. Open in a new tab FFAF by phenotype and sex. Men are in orange and women are in purple; full bars signify PVI-only treatment while hashed bars signify PVI + EGF-guided source ablation. There were no significant differences in outcomes by phenotype across the two sexes (n.b. data scarcity of female Type III patients receiving PVI + EGF-guided ablation) Lastly, multivariable Cox proportional hazards models were used to assess time to recurrence of AF or AF/AFL/AT. The Cox proportional hazards models were adjusted for covariates and stratified by patient group. Among all models, female sex was not associated with a significantly different hazard of AF recurrence or AF/AFL/AT recurrence in any patient group, as shown in Table 2 and Fig. 8 . Table 2. Cox proportional hazards comparing females to males by patient group Patient group AF hazard ratio and CI AF p -value AF/AFL/AT hazard ratio and CI AF/AFL/AT p -value No sources 2.07 [0.71, 6.02] 0.18 1.90 [0.72, 5.03] 0.20 Sources after PVI-only 0.71 [0.28, 1.82] 0.47 0.63 [0.25, 1.62] 0.34 Sources after PVI + EGF-guided ablation 0.62 [0.16, 2.42] 0.50 1.54 [0.51, 4.64] 0.44 Open in a new tab Hazard ratios and 95% CIs are reported for AF and a combined arrhythmia endpoint of AF, AFL, and AT. No statistically significant differences in hazard were observed between sexes in any group Fig. 8. Open in a new tab Cox proportional hazards model adjusted survival curves for AF recurrence (top) and AF/AFL/AT recurrence (bottom), stratified by sex. Curves represent predicted survival probabilities from models adjusted for sex within each phenotype group. Males are shown in orange and females in purple. Models were fit separately within each patient group: no source patient (left) , source patients after PVI-only (center), and source patients after PVI + source ablation (right) . The y-axis reflects the estimated probability of remaining free from recurrence over time, adjusted for covariates Similar trends by sex appear across factors that increase CHA 2 DS 2 -VASc scores at large Lastly, the potential relationships between the different demographics by sex and the observed phenotype distributions by sex were explored. Most notably, women were older than men, so the impact of age on phenotype distribution was first assessed. As shown in Table 3 , women were consistently older than men across all four phenotypes without a certain age group concentrating in any individual phenotype across both sexes. A multinomial logistic mixed-effects model further showed sex to have a 22-fold larger effect size on phenotype than age. Table 3. Age by patient phenotype and sex Phenotype All ( n = 104) Men ( n = 74) Women ( n = 30) Type I 64.6 ± 10.4 64.4 ± 11.2 65.5 ± 7.8 Type II 68.5 ± 10.0 65.9 ± 10.8 73.5 ± 5.7 Type III 65.9 ± 11.1 64.4 ± 11.5 71.8 ± 7.2 Type IV 61.6 ± 6.4 60.8 ± 5.6 63.9 ± 8.4 Open in a new tab Women were older than men across all phenotypes Despite age differences not driving the contrasting EGF phenotype distributions of men and women, there were still differences in ages across the phenotypes that arose independently within each sex. The largest age differences were between Type IV and Type II men ( p = 0.073) and between Type IV and Type II women ( p = 0.007). As such, older patients tended to have sources and healthier substrate within each group. Moreover, when looking more broadly at CHA 2 DS 2 -VASc scores that incorporate both age and sex, patients with sources had higher CHA 2 DS 2 -VASc scores than those without sources (2.7 ± 1.5 vs. 2.1 ± 1.3, p = 0.018), and patients with high EGFC had higher CHA 2 DS 2 -VASc scores than those with low EGFC (2.9 ± 1.2 vs. 2.2 ± 1.5, p = 0.004), as shown in Fig. 9 . In a multivariable linear regression, each of sources ( p = 0.020) and low EGFC (p = 0.005) remained independently associated with CHA₂DS₂-VASc score, and variance inflation factors (< 1.9) indicated low multicollinearity between them. Fig. 9. Open in a new tab CHA 2 DS 2 -VASc score by source and EGFC classifications. Mean and standard deviation are shown. CHA 2 DS 2 -VASc scores were higher in patients with sources vs. no sources and in those with high EGFC vs. low EGFC These effects were also maintained even when accounting for patient sex, as shown in detailed distribution plots colored by recurrence rate in Fig. 10 . Men with sources had a CHA 2 DS 2 -VASc of 2.2 ± 1.5 vs. 1.8 ± 1.4 in men with no sources; women with sources had a CHA 2 DS 2 -VASc of 3.7 ± 1.1 vs. 2.8 ± 0.9 in women with no sources. Similarly, men with low EGFC had a CHA 2 DS 2 -VASc of 2.4 ± 1.1 vs. 1.9 ± 1.5 in men with high EGFC; women with low EGFC had a CHA 2 DS 2 -VASc of 3.8 ± 0.8 vs. 3.1 ± 1.2 in men with high EGFC. Though both source patients and high EGFC patients had higher CHA 2 DS 2 -VASc scores, each of these EGF characteristics had countervailing effects on recurrence rate. Fig. 10. Open in a new tab CHA 2 DS 2 -VASc score distribution and FFAF by source classification and EGFC classification. Coloring is from red to blue with increasing rate of FFAF after PVI-only procedures among each of the four horizontal categories. Patients with sources had a higher distribution of CHA 2 DS 2 -VASc scores within each sex, as did patients with high EGFC, despite the differing effects of each on recurrence rate Discussion The primary findings of this paper are as follows: Women with PeAF or LS-PeAF were more likely to have extra-PV sources and healthy substrate when compared with men. Patients had no sex-specific differences in outcomes by phenotype, which included a higher FFAF after PVI + EGF-guided ablation vs. PVI-only among patients with sources as well as a higher FFAF among patients presenting with healthy substrate. Women were accordingly concentrated in phenotypes that maximally benefit from PVI + EGF-guided ablation for treatment of their AF. Higher CHA 2 DS 2 -VASc scores were also associated with source presence and healthy substrate across both sexes. Different AF mechanisms by sex may explain sex-based post-ablation outcomes Female sex has been tied to worse outcomes following PVI in both PAF and PeAF, but differences in the demographics of men versus women included in the trials have made interpretation of this observation difficult. Recently, a sex-specific analysis of the CAPLA trial demonstrated that women under 65 years old undergoing ablation for PeAF had twice the recurrence rate of men and were accordingly more likely to require a repeat procedure [ 37 ]. Our analysis of pooled PeAF and LS-PeAF EGF mapping patients suggests that this finding can be explained by a higher prevalence of extra-PV sources despite overall healthier substrate in women. To reach this conclusion, source presence and substrate health in men and women were analyzed via EGF mapping, which is a method of visualizing AF wavefront propagation patterns through the substrate. EGF mapping was developed to identify these temporally unstable sources that contribute to the pathophysiology of AF [ 25 , 32 ] and are especially common in PeAF and LS-PeAF patients [ 29 ]. It has since been prospectively tested in three clinical trials analyzed collectively in this paper: FLOW-AF [ 31 ], FLOW-EVAL AF [ 28 ], and the AF-FLOW Global Registry [ 29 ]. These trials collectively employed EGF mapping technology to target ablation of extra-PV sources and to quantify atrial myopathy via EGFC. When these two factors were combined, patients could be assigned EGF-based phenotypes that were predictive of their recurrence rate when coupled with their treatment modality regardless of sex. Accordingly, this pooled analysis of data from the three prospective clinical studies examined sex differences among the EGF phenotypes. Female patients were more than twice as likely as men to present as Type II with active sources but otherwise healthy conduction throughout their substrate. Consequently, women had nonsignicantly worse outcomes than men after receiving PVI-only but nonsignificantly better outcomes after PVI + EGF-guided source ablation, which was presumably because they had a higher likelihood of having extra-PV sources that warranted ablation beyond PVI but more organized underlying AF conduction patterns. Such results were encouraging, especially when considering the better outcomes despite the increased age of female patients. Indeed, among the Type II phenotype that women fell most heavily into, FFAF was 50% after PVI-only but 91% after PVI + EGF-guided source ablation. Source ablation also improved outcomes in Type III patients who had extra-PV sources but disorganized conduction throughout the substrate from 27 to 47% FFAF. Relationship to other studies The data presents a complex web of patterns that at times align with previous work, but in other moments, point in contrasting directions. Non-PV triggers have historically been found at higher rates in women, which were believed to result from increased structural remodeling in women [ 23 , 38 ]. However, this remodeling has also resulted in more low voltage areas [ 20 – 23 ], which would be perhaps expected to result in lower EGFC in women. Notwithstanding, these past studies importantly analyzed voltage in patients presenting for de novo ablation with women who had 50% or greater PAF. By contrast, the patients analyzed here are heavily concentrated in those receiving redo ablation and have 100% PeAF or long-standing PeAF. This population is therefore skewed toward individuals with diffuse fibrosis exceeding levels reported in prior studies for both sexes. Moreover, given that the current patient population has PeAF that was largely untreatable with initial PVI and that women have more extra-PV sources, it would follow that men have either more PV reconnections (Type I) or worse substrate health (Type III and Type IV) as their mechanism of disease compared to women. Lastly, it should be noted that EGFC measured in these patients does not 1:1 detect the presence of fibrosis but instead measures the conduction speeds of circuits through the fibrotic tissue. Implications of sources and substrate health for treatment strategies Despite the presence of more sources in women, there were no significant differences in extra-PV source locations between men and women. Most sources in both sexes were near the SVC/RA junction and the LAA. It is also worth noting that only 16% of sources were on the posterior wall. Such findings coincide with those prior studies that also demonstrated a small minority of source activity located on the posterior wall with instead a wide distribution of sources throughout the entire atria [ 37 , 39 ]. As such, there is growing evidence of a potential ceiling of efficacy for empiric posterior wall isolation or other non-targeted, empiric ablations given this source distribution. Among patients not containing substantially active sources, Type I patients had 100% FFAF after PVI-only, likely due to their lack of extra-PV sources and accompanying healthy substrate giving them no negative prognostic factors in their wavefront propagation patterns through their atria. By contrast, Type IV patients with abnormal substrate — a phenotype in which women were less concentrated than men—were found to have suboptimal outcomes post-PVI despite their absence of sources. Though not attempted in the studies presented herein, there are potential benefits for strategies that address abnormal substrate in Type III and Type IV patients. These include substrate homogenization or addition of antiarrhythmic drugs. Relationship of CHA 2 DS 2 -VASc components to EGF phenotypes Interestingly, just as female sex was associated with both sources and higher EGFC despite their opposing effects on recurrence rate, higher CHA 2 DS 2 -VASc scores more generally were also associated with these same factors. As female sex is just one component of the CHA 2 DS 2 -VASc score, the existence of the same phenotype trends among the remainder of the CHA 2 DS 2 -VASc score components in both men and women brings further physiological implications. For example, the presence of sources and/or healthy substrate may have mechanistic ties to the increased embolic stroke risk in AF as determined by the CHA 2 DS 2 -VASc score. Insofar as EGF phenotyping reflects underlying AF pathophysiology, factors that increase stroke risk including vascular endothelial damage and hypercoagulability may share common causes with AF source formation [ 26 ], while atrial conduction abnormalities that decrease EGFC are more likely to be driven by a separate mechanism and result in decreased ability for AF circuits to propagate through the entire endocardium and amplify regions of stasis [ 28 ]. After all, as source presence and substrate health are orthogonal variables in that they are not highly correlated to one another [ 40 , 41 ], independent mechanisms of pathology for sources and EGFC are expected. It should also be noted that although fibrosis also lowers EGFC, all patients in this study had persistent AF with relatively high baseline level of fibrosis, and source patients were above the threshold for high EGFC nonsignificantly more often than no source patients. Further study is needed to determine if source ablation can decrease stroke risk, especially among women. Future directions Overall, EGF mapping and phenotyping provide mechanistic insights that can guide optimal treatment for all patients. In this study, phenotype distribution differences between men and women were present but not driven by the increased age of female patients, while outcomes by phenotype did not vary significantly between the sexes. EGF phenotyping can consequently be employed to gain insights about disease mechanism and prognosis whereby the information from phenotype alone likely supersedes that gleanable from other demographic and clinical metrics, including patient age and sex. Because treatment response by phenotype is sex-independent, phenotype alone can then be used to determine the optimal treatment modality for the individual patient, which may include PVI-only or PVI + focal ablation strategies. Limitations The primary limitation of this analysis is the small number of patients analyzed across the three trials, which was heavily weighted towards FLOW-AF. Indeed, only 30 female PeAF patients were enrolled in prospective EGF studies that could be used for this analysis. Additionally, the patient population was not representative of AF allcomers, but it was restricted to PeAF patients, particularly a heavily redo population who investigators chose to enroll in an experimental mapping study. Thirdly, new ablation technologies and ablation strategies were not tested, including pulsed field ablation and PVI + posterior wall isolation. The ongoing RESOLVE-AF and upcoming OPTIMIZE clinical trials will therefore aid in determining if these findings are reproducible across an even broader cohort of male and female patients, including the mixed PAF and PeAF population present in RESOLVE-AF. OPTIMIZE will additionally focus for the first time on pulsed field ablation of EGF-identified sources, as well as on diverse patient recruitment for the purposes of assessing additional trends that may be present across race and ethnicity. Conclusion The EGF mapping differences and clinical outcomes at 1 year after EGF-identified source ablation among PeAF and LS-PeAF patients were assessed between men and women. Significant differences were seen in phenotype distribution between the sexes with women more likely to have a Type II EGF phenotype with extra-PV sources and healthy substrate. Recurrence rates were also significantly different between phenotypes with those undergoing PVI + source ablation significantly less likely to have AF recurrence than their counterparts receiving PVI alone. These insights into AF patient characteristics and ablation responses support the potential use of EGF mapping and phenotyping in clinical practice. The sex-specific variation in AF phenotypes also highlights the growing importance of considering sex-specific factors in AF management or treating towards patient-specific pathophysiology more generally. 6 Supplementary Information Below is the link to the electronic supplementary material. Supplementary file1 (DOCX 16 KB) (17KB, docx) Abbreviations AF Atrial fibrillation AFL Atrial flutter aOR Adjusted odds ratio AT Atrial tachycardia CI Confidence interval EGF Electrographic flow EGFC Electrographic flow consistency LA Left atrium LAA Left atrial appendage LS-PeAF Long-standing persistent AF FFAF Freedom from AF PAF Paroxysmal AF PeAF Persistent AF PV Pulmonary vein PVI PV isolation RA Right atrium SAC Source activity SVC Superior vena cava Declarations Ethics approval All clinical data was collected from clinical trials performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of participating institutions. Consent to participate Informed consent was obtained from all individual participants included in the study. Data Availability Clinical trial data is available at clinicaltrials.gov, IDs NCT04473963 , NCT06260670 , and NCT05481359 Competing interest KRN is a consultant for Cortex, Inc., Abbott, and Biosense/J&J. MHK is a former employee at Cortex, Inc. NM is a speaker/consultant for Medtronic, Boston Scientific, Syneos Health, and Abbott. SC is an employee at Cortex, Inc. Footnotes Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Ilana Kutinsky and Kent R. Nilsson contributed equally to the work. References 1. de Groot N, et al. Direct proof of endo-epicardial asynchrony of the atrial wall during atrial fibrillation in humans. Circ Arrhythm Electrophysiol. 2016;9(5):e003648. [ DOI ] [ PubMed ] [ Google Scholar ] 2. Lim HS, et al. 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Supplementary Materials Supplementary file1 (DOCX 16 KB) (17KB, docx) Data Availability Statement Clinical trial data is available at clinicaltrials.gov, IDs NCT04473963 , NCT06260670 , and NCT05481359 Articles from Journal of Interventional Cardiac Electrophysiology are provided here courtesy of Springer ACTIONS View on publisher site PDF (1.7 MB) Cite Collections Permalink RESOURCES Similar articles Cited by other articles Links to NCBI Databases Follow NCBI NCBI on X (formerly known as Twitter) NCBI on Facebook NCBI on LinkedIn NCBI on GitHub NCBI RSS feed Connect with NLM NLM on X (formerly known as Twitter) NLM on Facebook NLM on YouTube National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894 Web Policies FOIA HHS Vulnerability Disclosure Help Accessibility Careers NLM NIH HHS USA.gov Back to Top
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